Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Abstract

In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field's increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.

Chronic chemogenetic activation of forebrain excitatory neurons in postnatal life evokes long-lasting changes in mood-related behavior

“…In this regard, both the MS and PNFLx models have critical periods spanning from P2-14 and P2-11 respectively 74,76,77 . These temporal windows overlap with distinct critical periods including the stress hyporesponsive period 107-109 , a neurodevelopmental window for the refinement of multiple cortical circuits 1,2 , including the maturation of serotonergic afferents to the cortex 110,111 , and the tuning of excitation-inhibition balance across cortical microcircuits 34,112,113 . A recent report indicates that hM3Dq DREADD activation of the medial prefrontal cortex during postnatal life can abrogate the influence of maternal separation on oligodendrogenesis and despair-like behavior 83 .…”

“…Strikingly, a commonality noted across these animal models is the fact that multiple molecular, cellular, functional and behavioral changes often persist throughout the animal's lifespan 5,11,25 . Amongst the underlying mechanisms implicated in the establishment of such long-lasting changes in response to early life perturbations are a dysregulation of the hormonal stress response pathway 22,26-30 , serotonergic system 31-33 , and emergence of excitation-inhibition balance within key cortical neurocircuits 34,35 .…”

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

“…However, coming to a better understanding of how E:I balance is affected across a heterogeneous mixture of autistic individuals has proven to be challenging because of the limited availability of robust E:I biomarkers that are non-invasive and applicable in humans and which can be measured on a large scale. A majority of the literature about E:I balance in autism extends from investigations of prominent single gene mutations associated with autism and the animal model research around these genes 2,3 . This leaves a significant gap in evaluating the E:I theory on a larger majority of the autistic population.…”

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

“…A variety of in vivo studies have demonstrated that non-competitive NMDAr antagonism increases the firing rate of PFC pyramidal neurons reducing their synchrony, and enhancing broadband gamma activity 33,[46][47][48][49] . This broadband gamma enhancement is thought of as an aberrant and diffuse noise at the network level that can cause dysfunction in cognitive and sensory-motor integration 17,50 . In our study, gamma increase after KET injection was robust in the PFC, with subtle effects in the HPC (see also Figure S1A).…”